CN115452911B - A MEMS detection sensor and detection method - Google Patents
A MEMS detection sensor and detection method Download PDFInfo
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Abstract
本发明属于生物分子检测用传感器技术领域，具体为一种具有检测功能的MEMS传感器及检测方法，能够在传感器敏感单元表面组装分子层膜用来特异性结合被检测物质，并将二者特异性结合前后的信号变化转化为电信号输出实现检测，解决了传统PCR以及ELISA检测方法中采用荧光标记带来的操作复杂、检测效率低的技术问题。
The present invention belongs to the technical field of sensors for biomolecule detection, and specifically relates to a MEMS sensor with detection function and a detection method, which can assemble a molecular layer membrane on the surface of the sensor sensitive unit to specifically bind to the substance to be detected, and convert the signal changes before and after the specific binding of the two into electrical signal output for detection, thereby solving the technical problems of complex operation and low detection efficiency caused by the use of fluorescent labels in traditional PCR and ELISA detection methods.
Description
Technical Field
The invention relates to the technical field of sensors for biomolecule detection, in particular to a MEMS sensor with a detection function and a detection method, which can assemble a molecular layer film on the surface of a sensor sensitive unit for specifically combining a detected substance, convert signal changes before and after the specific combination of the sensor sensitive unit and the detected substance into electric signals for output, and realize the novel sensor with the detection function and the detection method.
Background
Molecular detection refers to a technique for diagnosing by detecting changes in the structure or expression level of genetic material in a patient using molecular biological methods. Molecular detection is the main method of predictive diagnosis, and can be used for diagnosing individual genetic diseases and prenatal diagnosis. Molecular diagnostics refers primarily to the detection of genes encoding various structural proteins, enzymes, antigen antibodies, immunologically active molecules associated with disease.
The conventional detection methods commonly used in the current molecular detection comprise PCR, ELISA, electron microscope technology, gene chip and the like. PCR, also known as the polymerase chain reaction, is a method for rapidly amplifying gene fragments in vitro, and can amplify specific gene fragments in a small amount of genomic DNA or RNA sample by millions of times in a short time, with high specificity and accuracy. ELISA is also called enzyme-linked immunosorbent assay, which refers to a qualitative and quantitative detection method in which soluble antigen or antibody is bound to a solid carrier such as polystyrene, and an immune reaction is performed by utilizing the specific binding of antigen and antibody.
PCR and ELISA are currently more commonly used rapid detection means for food pathogens, but because the two methods need to use a fluorescent labeling method, detection functions are realized through a series of complex biochemical treatment processes, the operation is complicated, the hybridization time is long, a few hours or even a few days are often needed, the detection time of the pathogens is not fundamentally reduced, the detection speed is improved, and the requirements of actual rapid detection are difficult to meet due to high probe labeling and modification costs.
Therefore, aiming at the technical problems of long detection time and low sensitivity of the sensor in the detection process in the current molecular detection field, a scheme is needed to solve the problems in the prior art.
MEMS sensors, i.e. microelectromechanical systems, are new types of sensors that are fabricated using microelectronics and micromachining techniques. Compared with the traditional sensor, the sensor has the characteristics of small volume, light weight, low cost, low power consumption, high reliability, suitability for mass production, easy integration and realization of intelligence. At the same time, feature sizes on the order of microns allow it to perform functions not possible with some conventional mechanical sensors. As a novel detection technology, the MEMS sensor has the characteristics of high detection speed, high sensitivity, strong practicability and low cost detection, gradually becomes a focus of attention in the fields of various molecular detection, biomedicine, chemistry, environmental engineering and the like, and is receiving more and more attention and research.
Disclosure of Invention
The invention provides a MEMS detection sensor which at least can solve part of problems existing in the prior art.
In order to solve the technical problems, according to one aspect of the present invention, the following technical solutions are provided:
A MEMS detection sensor comprising a sensor unit and a piezoelectric module, the piezoelectric module being disposed on one side of the sensor unit;
The sensor unit comprises an upper conductive plate, a lower conductive plate and a supporting structure, wherein the upper conductive plate of the sensor unit is in a suspended state under the support of the supporting structure, an aptamer molecular layer film for specific combination is arranged on the surface of the upper conductive plate, and after the aptamer molecular layer film is specifically combined with a substance to be detected, the relative area and/or the relative distance between the upper conductive plate and the lower conductive plate are changed.
As a preferable scheme of the MEMS detection sensor, the sensor unit is arranged above a substrate and is arranged in an array structure, and comprises a detection unit and a reference unit, wherein the detection unit and the reference unit are arranged adjacent to each other on the substrate.
As a preferable scheme of the MEMS detection sensor, the support structure comprises a pillar structure and a snake-shaped beam structure which are connected with each other, wherein two ends of the snake-shaped beam structure are respectively connected with an upper conducting plate and the pillar structure, the lower conducting plate is arranged on the surface of the substrate, the pillar structure is arranged at the outer edge of the lower conducting plate, and two sides of the upper conducting plate are respectively connected with the snake-shaped beam structure.
As a preferable scheme of the MEMS detection sensor, the piezoelectric module is connected with an alternating electric field.
As a preferable scheme of the MEMS detection sensor, the connecting line between two ends of the serpentine beam structure and the central connecting line of the upper conducting plate and the lower conducting plate are the same straight line.
As a preferable scheme of the MEMS detection sensor, the surface of the upper conducting plate is also provided with a sensitive layer.
As a preferable scheme of the MEMS detection sensor, the sensitive layer is made of any one of metal and two-dimensional materials.
As a preferable scheme of the MEMS detection sensor, the surface of the upper conducting plate of the reference unit is provided with an antifouling molecular layer for preventing nonspecific binding.
In order to solve the above technical problems, according to another aspect of the present invention, the following technical solutions are provided:
A method of detecting a MEMS detection sensor, comprising the steps of:
applying an alternating electric field to a piezoelectric module of the MEMS detection sensor, and immersing the piezoelectric module into a solution to be detected containing a substance to be detected;
setting detection temperature and detection time to enable the sensor unit to be fully combined with the substance to be detected;
and obtaining the detection limit of the substance to be detected according to the detection results of the detection unit and the reference unit.
As a preferable scheme of the detection method of the MEMS detection sensor, the method for obtaining the detection limit of the substance to be detected according to the detection results of the detection unit and the reference unit comprises the following steps:
Gradually increasing the concentration of a substance to be detected in the solution to be detected from zero, adding the solution to be detected to the surface area of the sensitive film of the detection unit, comparing the color change and the degree of the surfaces of the detection unit and the reference unit, and obtaining the detection limit of the substance to be detected of the detection unit through calculation.
The beneficial effects of the invention are as follows:
1. The invention provides a novel MEMS detection sensor structure, which utilizes an aptamer molecular layer film on the surface of a sensor to specifically combine substances to be detected, converts signal changes before and after detection into electric signals for output, does not need to adopt the traditional PCR and ELISA detection methods to carry out fluorescence labeling operation, can greatly reduce detection operation and detection time, greatly improves detection efficiency and detection sensitivity, and can reach ng/ml.
2. The MEMS detection sensor provided by the invention comprises a detection unit and a reference unit, wherein the surface of the detection unit is provided with a sensitive layer metal film and an aptamer molecular layer film, the specific combination of substances to be detected can be carried out, the surface of the reference unit is modified with an antifouling molecular layer, the non-specific combination of the substances to be detected can be prevented, the detection signal of the reference unit can be used as noise, the detection limit of the substances to be detected can be calculated through the detection difference values of the detection unit and the reference unit, the detection operation is simple, and the detection efficiency and the detection precision are obviously improved.
3. The piezoelectric driving mode has the advantages of simple structure, low power consumption, high response speed, high temperature resistance and high anti-interference capability compared with other driving modes.
4. By applying an alternating electric field on the piezoelectric module, the piezoelectric crystal lattice is changed under the action of the electric field to cause integral mechanical vibration, so that shearing force in the X-Y direction is generated on the sensor array, and the shearing force in the X-Y direction has no component in the Z-axis direction, so that sound wave energy cannot be vertically dissipated into liquid, the sound wave energy is ensured to be limited on the surface of a chip, the minimum energy attenuation can be kept in a liquid phase detection environment, and the detection of target substances is realized. The shear force also effectively removes non-specifically bound material after the material to be detected is added to the sensor array, thereby improving the authenticity and accuracy of the detection.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to the structures shown in these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic diagram of an MEMS detection sensor array structure according to the present invention;
FIG. 2 is a schematic diagram of a MEMS detection sensor unit structure according to the present invention;
FIG. 3 is a schematic diagram of the structure of a detection unit and a reference unit of the MEMS detection sensor unit of the present invention;
Fig. 4 is a schematic diagram of the detection principle of the MEMS detection sensor according to the present invention.
Reference numerals illustrate:
1-sensor unit, 2-piezoelectric module, 3-detection unit, 4-reference unit, 5-base plate, 6-upper conductive plate, 7-lower conductive plate, 8-pillar structure, 9-snake beam structure, 10-aptamer molecular layer film, 11-antifouling molecular layer, 12-specific conjugate and 13-sensitive layer.
The achievement of the objects, functional features and advantages of the present invention will be further described with reference to the accompanying drawings, in conjunction with the embodiments.
Detailed Description
The following description will be made clearly and fully with reference to the technical solutions in the embodiments, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
It should be noted that, if a directional instruction (such as up, down, left, right, front, and rear) is involved in the embodiment of the present invention, the directional instruction is merely used to explain the relative positional relationship, movement conditions, and the like between the components in a specific posture (as shown in the drawings), and if the specific posture is changed, the directional instruction is correspondingly changed.
In addition, if there is a description of "first", "second", etc. in the embodiments of the present invention, the description of "first", "second", etc. is for descriptive purposes only and is not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include at least one such feature. In addition, the technical solutions of the embodiments may be combined with each other, but it is necessary to base that the technical solutions can be realized by those skilled in the art, and when the technical solutions are contradictory or cannot be realized, the combination of the technical solutions should be considered to be absent and not within the scope of protection claimed in the present invention.
The MEMS detection sensor and the detection method provided by the invention can conveniently and rapidly realize concentration detection of a substance to be detected, and the detection method is simple in operation and excellent in detection sensitivity and accuracy.
A MEMS detection sensor comprising a sensor unit and a piezoelectric module, the piezoelectric module being disposed on one side of the sensor unit;
The sensor unit comprises an upper conductive plate, a lower conductive plate and a supporting structure, wherein the upper conductive plate of the sensor unit is in a suspended state under the support of the supporting structure, an aptamer molecular layer film for specific combination is arranged on the surface of the upper conductive plate, and after the aptamer molecular layer film is specifically combined with a substance to be detected, the relative area and/or the relative distance between the upper conductive plate and the lower conductive plate are changed.
The sensor units are arranged above the substrate and are arranged in an array structure, and each sensor unit comprises a detection unit and a reference unit, and the detection unit and the reference unit are arranged adjacent to each other on the substrate.
The support structure comprises a pillar structure and a snake-shaped beam structure which are connected with each other, wherein two ends of the snake-shaped beam structure are respectively connected with an upper conducting plate and the pillar structure, the lower conducting plate is arranged on the surface of the substrate, the pillar structure is arranged at the outer edge of the lower conducting plate, and two sides of the upper conducting plate are respectively connected with the snake-shaped beam structure. The piezoelectric module is connected with the alternating electric field. The connecting line between the two ends of the serpentine beam structure and the central connecting line of the upper conducting plate and the lower conducting plate are in the same straight line. The surface of the upper conducting plate is also provided with a sensitive layer. The sensitive layer is made of any one of metal and two-dimensional materials, and specifically, the sensitive layer is a metal film, and the metal film of the sensitive layer can be a gold film. The surface of the upper conductive plate of the reference unit is provided with an antifouling molecular layer for preventing nonspecific binding.
The upper conductive plate is suspended through the supporting structure and is separated from the lower conductive plate by a certain distance, after a substance to be detected is specifically combined with the aptamer molecular layer film, the mass load on the surface of the detection unit is changed, the relative area between the upper conductive plate and the lower conductive plate is changed, the change of capacitance is further generated, and the concentration of the substance to be detected can be calculated according to the difference value of the change of the load of the substance to be detected.
The detection sensor is provided with a piezoelectric module, and the piezoelectric module is utilized to drive the whole sensor array. By applying an alternating electric field to the piezoelectric module, the piezoelectric crystal lattice is changed under the action of the electric field to cause integral mechanical vibration, so that X-Y shearing force is generated on the sensor array, and the minimum energy attenuation can be kept in a liquid phase detection environment. The shear force also effectively removes non-specifically bound material after the material to be detected is added to the sensor array, thereby improving the authenticity and accuracy of the detection.
According to another aspect of the invention, the invention further provides a detection method of the detection sensor.
A method of detecting a MEMS detection sensor, comprising the steps of:
applying an alternating electric field to a piezoelectric module of the MEMS detection sensor, and immersing the piezoelectric module into a solution to be detected containing a substance to be detected;
setting detection temperature and detection time to enable the sensor unit to be fully combined with the substance to be detected;
and obtaining the detection limit of the substance to be detected according to the detection results of the detection unit and the reference unit.
The step of obtaining the detection limit of the substance to be detected according to the detection results of the detection unit and the reference unit comprises the following steps:
Gradually increasing the concentration of a substance to be detected in the solution to be detected from zero, adding the solution to be detected to the surface area of the sensitive film of the detection unit, comparing the color change and the degree of the surfaces of the detection unit and the reference unit, and obtaining the detection limit of the substance to be detected of the detection unit through calculation.
A sensitive layer metal film or a two-dimensional material layer, such as a gold film, is further arranged on the upper conductive plate, so that the surface activity of the upper conductive plate can be enhanced.
Example 1
Embodiment 1 of the present invention provides a MEMS detection sensor as shown in fig. 1-4.
A MEMS detection sensor comprising a sensor unit 1 and a piezoelectric module 2, the piezoelectric module 2 being arranged on one side of the sensor unit 1;
the sensor unit 1 comprises an upper conductive plate 6, a lower conductive plate 7 and a supporting structure, the upper conductive plate 6 of the sensor unit 1 is in a suspended state under the support of the supporting structure, an aptamer molecular layer membrane 10 for specific binding is arranged on the surface of the upper conductive plate 6, and after the aptamer molecular layer membrane 10 is specifically bound with a substance to be detected, the relative area and/or the relative distance between the upper conductive plate 6 and the lower conductive plate 7 are changed.
The sensor unit 1 is arranged above the substrate 5 and is arranged in an array structure, the sensor unit 1 comprises a detection unit 3 and a reference unit 4, and the detection unit 3 and the reference unit 4 are arranged adjacent to each other on the substrate 5.
The support structure comprises a pillar structure 8 and a snake-shaped beam structure 9 which are connected with each other, wherein two ends of the snake-shaped beam structure 9 are respectively connected with an upper conducting plate 6 and the pillar structure 8, the lower conducting plate 7 is arranged on the surface of the base plate 5, the pillar structure 8 is arranged at the outer edge of the lower conducting plate 7, and two sides of the upper conducting plate 6 are respectively connected with the snake-shaped beam structure 9.
The piezoelectric module 2 is connected with an alternating electric field. The connecting line between the two ends of the serpentine beam structure 9 and the central connecting line of the upper conductive plate 6 and the lower conductive plate 7 are the same straight line. The surface of the upper conducting plate 6 is also provided with a sensitive layer 13, and the sensitive layer 13 is a gold film. The upper conductive plate 6 surface of the reference cell 4 is provided with a layer 11 of anti-fouling molecules that prevents non-specific binding.
Example 2
The embodiment 2 of the invention provides a detection method of a MEMS detection sensor.
A method of detecting a MEMS detection sensor, comprising the steps of:
applying an alternating electric field to a piezoelectric module of the MEMS detection sensor, and immersing the piezoelectric module into a solution to be detected containing a substance to be detected;
setting detection temperature and detection time to enable the sensor unit to be fully combined with the substance to be detected;
and obtaining the detection limit of the substance to be detected according to the detection results of the detection unit and the reference unit.
The step of obtaining the detection limit of the substance to be detected according to the detection results of the detection unit and the reference unit comprises the following steps:
Gradually increasing the concentration of a substance to be detected in the solution to be detected from zero, adding the solution to be detected to the surface area of the sensitive film of the detection unit, comparing the color change and the degree of the surfaces of the detection unit and the reference unit, and obtaining the detection limit of the substance to be detected of the detection unit through calculation.
The detection unit surface is provided with the aptamer molecular layer film, the aptamer molecular layer film comprises a magnetic ball for capturing cancer cell antibodies, the specific binding of cancer cells of substances to be detected can be carried out, the surface of the reference unit is modified with the anti-fouling molecular layer, the anti-fouling molecular layer is serum protein, the non-specific binding of the substances to be detected can be prevented, the measured value of the reference electrode is used as noise, the concentration of the substances to be detected can be calculated through the detection difference value of the detection unit and the reference unit, the detection operation is simple, the detection efficiency and the detection precision are obviously improved, and the detection sensitivity can reach ng/ml.
By applying an alternating electric field to the piezoelectric module, the piezoelectric crystal lattice is changed under the action of the electric field to cause integral mechanical vibration, so that X-Y shearing force is generated on the sensor array, and the minimum energy attenuation can be kept in a liquid phase detection environment. The shear force also effectively removes non-specifically bound material after the material to be detected is added to the sensor array, thereby improving the authenticity and accuracy of the detection.
The foregoing description is only of the preferred embodiments of the present invention and is not intended to limit the scope of the invention, and all equivalent structural changes made by the content of the present invention or direct/indirect application in other related technical fields are included in the scope of the present invention.
Claims (10)
1. The MEMS detection sensor is characterized by comprising a sensor unit (1) and a piezoelectric module (2), wherein the piezoelectric module (2) is arranged on one side of the sensor unit (1);
The sensor unit (1) comprises an upper conducting plate (6), a lower conducting plate (7) and a supporting structure, wherein the upper conducting plate (6) of the sensor unit (1) is in a suspended state under the support of the supporting structure, an aptamer molecular layer film (10) for specific binding is arranged on the surface of the upper conducting plate (6), and after the aptamer molecular layer film (10) is specifically bound with a substance to be detected, the relative area and/or the relative distance between the upper conducting plate (6) and the lower conducting plate (7) are changed.
2. A MEMS detection sensor according to claim 1, characterized in that the sensor unit (1) is arranged above the substrate (5) and in an array configuration, the sensor unit (1) comprising a detection unit (3) and a reference unit (4), the detection unit (3) and the reference unit (4) being arranged adjacent to each other on the substrate (5).
3. The MEMS sensor of claim 2, wherein the support structure comprises a pillar structure (8) and a serpentine beam structure (9) which are connected with each other, wherein two ends of the serpentine beam structure (9) are respectively connected with an upper conductive plate (6) and the pillar structure (8), the lower conductive plate (7) is arranged on the surface of the substrate (5), the pillar structure (8) is arranged at the outer edge of the lower conductive plate (7), and two sides of the upper conductive plate (6) are respectively connected with the serpentine beam structure (9).
4. A MEMS detection sensor according to claim 1, characterized in that the piezoelectric module (2) is connected to an alternating electric field.
5. A MEMS sensor according to claim 3, wherein the line between the ends of the serpentine beam structure (9) is collinear with the central line of the upper conductive plate (6) and the lower conductive plate (7).
6. A MEMS detection sensor according to claim 1, characterized in that the upper conductive plate (6) surface is further provided with a sensitive layer (13).
7. The MEMS sensor as claimed in claim 6, wherein the sensitive layer (13) is made of any one of metal and two-dimensional material.
8. A MEMS detection sensor according to claim 2, characterized in that the upper conductive plate (6) surface of the reference cell (4) is provided with a layer (11) of anti-fouling molecules preventing non-specific binding.
9. The detection method of a MEMS detection sensor according to any one of claims 1-8, comprising the steps of:
applying an alternating electric field to a piezoelectric module of the MEMS detection sensor, and immersing the piezoelectric module into a solution to be detected containing a substance to be detected;
setting detection temperature and detection time to enable the sensor unit to be fully combined with the substance to be detected;
and obtaining the detection limit of the substance to be detected according to the detection results of the detection unit and the reference unit.
10. The detection method of the MEMS detection sensor according to claim 9, wherein the step of deriving the detection limit of the substance to be detected based on the detection results of the detection unit and the reference unit comprises the steps of:
Gradually increasing the concentration of a substance to be detected in the solution to be detected from zero, adding the solution to be detected to the surface area of the sensitive film of the detection unit, comparing the color change and the degree of the surfaces of the detection unit and the reference unit, and obtaining the detection limit of the substance to be detected of the detection unit through calculation.
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